The object of this proposal is to determine whether treatment of rheumatoid arthritis (RA) with a combination of fish oil and borage seed oil is superior to treatment with either oil alone. Fish oil is rich in the antiinflammatory n3 unsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and borage oil contains gammalinolenic acid (GLA), an n6 unsaturated fatty acid with antiinflammatory and immunomodulatory properties. Administration of borage oil and offish oil both suppress the clinical manifestations of RA. Animal studies indicate that the mechanisms whereby fish oil suppresses inflammation are both similar to and different from the means by which GLA reduces inflammation and that the combination treatment is more effective than each treatment alone. This proposal is for a multi-center, two year, phase 3, double-masked, placebo-controlled trial of 375 patients, which includes 4 treatment groups: 1) corn oil as a polyunsaturated fatty acid control; 2) fish oil; 3) borage oil; 4) fish oil plus borage oil. Radiographic analysis (Sharp Scores) of hands and feet will be done at baseline, 12, and 24 months. Biochemical and molecular mechanisms whereby the fatty acid treatments influence activation of monocytes (cytokine and oxygen radical generation), and T lymphocytes (proliferation, cytokine production, Thl/Th2 skewing, signaling events) will be investigated. Results of the cell activation (ex vivo) studies will be correlated with clinical outcomes. Results of these studies should raise awareness of the usefulness of naturally occurring oils in inflammatory diseases, lead to more rational use of fatty acids in treatment of inflammatory arthritis, and provide a greater understanding of the mechanisms of action of antiinflammatory fatty acids.